Aromatase promoter I.f is regulated by estrogen receptor alpha (ESR1) in mouse hypothalamic neuronal cell lines

M. Bertan Yilmaz, Andrew Wolfe, You Hong Cheng, Christine Glidewell-Kenney, J. Larry Jameson, Serdar E. Bulun

Research output: Contribution to journalArticle

Abstract

Aromatase (CYP19A1) catalyzes the conversion of C19 steroids to estrogens. Aromatase and its product estradiol (E2) are crucial for the sexually dimorphic development of the fetal brain and the regulation of gonadotropin secretion and sexual interest in adults. The regulation of aromatase expression in the brain is not well understood. The aromatase (Cyp19a1) gene is selectively expressed in distinct neurons of the hypothalamus through a distal brain-specific promoter I.f located ∼36 kb upstream of the coding region. Here, we investigated a short feedback effect of E2 on aromatase mRNA expression and enzyme activity using estrogen receptor alpha (ESR1; also known as ERalpha)-positive or ESR1-negative mouse embryonic hypothalamic neuronal cell lines that express aromatase via promoter I.f. Estradiol regulated aromatase mRNA expression and enzyme activity in a time- and dose-dependent manner, whereas an E2 antagonist reversed these effects. The nucleotide -200/-1 region of promoter I.f conferred E2 responsiveness. Two activator protein 1 (AP-1) elements in this region were essential for induction of promoter activity by E2. ESR1 and JUN (c-Jun) bound to these AP-1 motifs in intact cells and under cell-free conditions. The addition of an ESR1 mutant that interacts with JUN but not directly with DNA enhanced E2-dependent promoter I.f activity. Independently, we demonstrated an interaction between ESR1 and JUN in hypothalamic cells. Knockdown of ESR1 abolished E2-induced aromatase mRNA and enzyme activity. Taken together, E2 regulates Cyp19a1 expression via promoter I.f by enhanced binding of an ESR1/JUN complex to distinct AP-1 motifs in hypothalamic cells. We speculate that this mechanism may, in part, regulate gonadotropin secretion and sexual activity.

Original languageEnglish (US)
Pages (from-to)956-965
Number of pages10
JournalBiology of reproduction
Volume81
Issue number5
DOIs
StatePublished - 2009

Keywords

  • Aromatase
  • Brain
  • Estradiol
  • Estradiol receptor
  • Estrogen receptor 1
  • Hypothalamus
  • Mechanisms of hormone action
  • Neuron
  • Promoter I.f
  • c-Jun

ASJC Scopus subject areas

  • Reproductive Medicine
  • Cell Biology

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  • Cite this

    Yilmaz, M. B., Wolfe, A., Cheng, Y. H., Glidewell-Kenney, C., Jameson, J. L., & Bulun, S. E. (2009). Aromatase promoter I.f is regulated by estrogen receptor alpha (ESR1) in mouse hypothalamic neuronal cell lines. Biology of reproduction, 81(5), 956-965. https://doi.org/10.1095/biolreprod.109.077206